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  • br Conclusion Infections caused by the P

    2021-09-18


    Conclusion Infections caused by the P. aeruginosa could not be cured by current antibiotics, making multiple drug resistance of P. aeruginosa an increasing threat for human lives. Looking for a new therapeutic mechanism for infections caused by the P. aeruginosa has become a central issue. There may be broad prospects for HemO inhibitors to treat P. aeruginosa related infections. However, more studies are warranted to further explore new ways to suppress heme utilization in P. aeruginosa and to apply the HemO inhibitors to clinic.
    Declarations of interest
    Ethical approval
    Informed consent
    Introduction Heme oxygenase (HO) catalyzes the first and rate-limiting enzymatic step of heme degradation to produce carbon monoxide (CO), iron and biliverdin, which is converted into bilirubin via biliverdin reductase [[1], [2], [3], [4]]. HO-1, the inducible isoform of HO, provides antioxidant protection and exerts major immuno-modulatory functions in macrophages by promoting anti-inflammatory effects [4,5]. For example, earlier work has demonstrated an increased susceptibility of HO-1 knockout mice to inflammation and that HO-1 controls interferon-β production in a conditional knockout mouse model lacking HO-1 in myeloid adenosine monophosphate synthesis [[6], [7], [8]]. In addition, the HO-1 pathway is regulated via the anti-inflammatory mediator interleukin (IL)-10 [9], and also inhibits the generation of pro-inflammatory markers such as TNF-α and IL-1β [6,10]. Importantly, specific interactions of HO-1 with its substrate heme appear to be critical for differentiation and inflammatory activation of macrophages [[11], [12], [13], [14]]. HO-1 is up-regulated by heme and numerous stress stimuli. Its expression is governed by a complex network of signaling cascades and transcriptional regulators including BTB and CNC homology 1 (BACH1) and NRF2, which act as repressor and activator of the HO-1 gene, respectively [5,15]. In particular, BACH1 is a heme sensor protein that loses its repressing activity following increased intracellular heme levels and heme binding. Furthermore, high levels of heme induce degradation of BACH1 [[16], [17], [18]]. It is known that HO-1 expression by the prototypical pro-inflammatory activator lipopolysaccharide (LPS), a Toll-like receptor (TLR)4 activator, is regulated in coordination with BACH1 in human macrophages [19,20]. Although the underlying mechanisms of this pathway are largely unknown, the crucial role of heme in the modulation of BACH1 suggests it could also be a central factor that determines BACH1/HO-1 regulation in inflammation. The intracellular heme pool can be principally categorized into fractions of exchange-inert heme and labile heme [[21], [22], [23]]. In contrast to exchange-inert heme, which is covalently or non-covalently bound to hemoproteins (eg. cytochrome c and myoglobin), labile heme is redox-active heme that is loosely bound to proteins other than hemoproteins [22,24]. Notably, endogenous heme from the labile heme pool can be rapidly mobilized for signaling and other heme-dependent cellular processes and, thus, has also been designated regulatory heme [21,23,25,26]. Increased levels of heme in the circulation, due to hemolysis or tissue damage, have also been proposed to exert signaling functions by binding to pattern recognition receptors such as TLR4 in macrophages and inducing an adaptive immune response [27,28]. Conversely, whether TLR4 activation by inflammatory stimuli affects the homeostasis of intracellular heme has not been examined.
    Materials and methods
    Results
    Discussion In keeping with previous findings by us and others [19,20], we corroborate in this study a counter-regulatory adenosine monophosphate synthesis pattern of LPS-dependent BACH 1 and HO-1 expression in human and mouse macrophages. We attribute this peculiar response to the novel observation reported herein showing that LPS exerts an opposing effect on intracellular labile heme: in fact, heme levels are down-regulated in human macrophages resulting in accumulation of BACH1 and consequent HO-1 repression while the labile heme pool is raised in mouse cells leading to BACH1 disappearance and induction of HO-1. Why LPS causes a differential fluctuation in labile heme in the two cell types is unclear at present but our experiments using the TLR4 antagonist TAK-242 in human cells point to activation of TLR4 as directly responsible for the changes in heme levels as well as expressions of BACH1 and HO-1 (Fig. 8). We note that a detailed study on TLR4-dependent gene regulation in human and mouse macrophages has revealed extensive divergence in regulatory patterns of orthologue genes in these cells, which appear to be linked with evolutionary-dependent structural differences in various gene promoters [39]. Accordingly, a number of functionally relevant differences between the human and mouse HO-1 promoters have been described, including a GT repeat in the proximal promoter region of the human HO-1 gene [[40], [41], [42]]. Remarkably, iNOS regulation also exhibits a different interspecies-specific expression pattern in murine and human macrophages [43,44]. Interestingly, our data highlight that this divergence is evident only under TLR4 activation conditions since HO-1 and BACH1 regulation following exposure to exogenous heme is identical in the two cell types and is not affected by TAK-242 in hMDMs.